4-phenyl-1, 2, 3, 6-tetrahydropyridine-1-alkanoic acid amides



l-PHENYL-l,2,3,6-TETRAHYDROPYRIDINE-l- ALKANOEC ACID AMIDES Paul AdriaanJan Janssen, Vosselaar, near Turnhout, Belgium Application December 22,1958 Serial No. 781,881

9 Claims. (Cl. 260-295) No Drawing.

This invention relates to tetrahydropyridine derivatives. The novelcompounds are 4-phenyl-l,2,3,6-tetrahydropyridine-l-alkanoic acid amidesof the general structural formula and the non-toxic salts thereof,wherein A is a cyclopentyl, cyclohexyl, phenyl, fiurophenyl,chlorophenyl, bromophenyl, iodophenyl, nitrophenyl, or tolyl radical,wherein B is a hydrogen or lower alkyl radical, and wherein Alk is alower aikylene radical.

Among the radicals which B can represent are such lower alkyl groups asmethyl, ethyl, propyl, butyl, pentyl,

and hexyl, wherein the propyl, butyl, pentyl, and hexyl The compounds ofthis invention are valuable pharmaceutical agents. They are potentdepressants of the central nervous system. They potentiate barbitturatehypnosis and inhibit the righting reflex in experimental ani- 5 mals.

ride, propyl chloride, butyl chloride, isobutyl chloride,

benzyl chloride and bromide, phenethyl bromide, naphthylmethyl chloride,dimethyl sulfate, diethyl sulfate, methyl benzene-sulfonate, ethyltoluenesulfonate, ethylenechlorohydrin, propylenechlorohydrin, allylbromide, methallyl bromide and crotyl bromide.

The compounds of this invention can be prepared by condensing anappropriately selected haloalkanoic acid amide of the formula NCO-Alk-Halogen B Y with 4-phenyl-1,2,3,6-tetrahydropyridine, wherein A,B,

and Alk are defined as above. The reaction can be carried on'in an inertsolvent such as an aromatic hydrocarbon (e.g. benzene, toluene), a loweralkanol. (e g. jethanol, butanol), a lower alkanone (e.g'. butanone,

, Halogen Co-Alk-Halogen wherein A, B, and Alk are defined as above.

The compounds which constitute this invention and the methods for theirpreparation will appear more fully from a consideration of the followingexamples, which are given for the purpose of illustration only and arenotto be construed as limiting the invention in spirit or in scope. Inthese examples quantities are given in parts by weight and temperaturesin degrees centigrade Example 1 In a bomb 2 mixture of 9.5 partsof'N-cycloh'exyl-pchloropropionamide, 15.9 parts of4-phenyl-l,2,3,6-tetrahydropyridine, and 0.1 part of potassium iodide inparts of toluene is heated for 50 hours at a temperature 'of 140-150 C.The contents of the bomb are cooled and filtered. The filtrate istreated with a mixture of 500 parts of 10% hydrochloric acid and 400parts of ether to yield the hydrochloride which is then collected on afilter and'washed with ether. A second crop is obtained by passinganhydrous hydrogen chloride gas through the etheric solution. Theproduct is collected on a filter and recrystallized from isopropanol. Inthis manner there is obtainedN-cyclohexyl-fi-(4-phenyl-l,2,3,6-tetrahydropyridine)propionamidehydrochloride melting at 2182l9.5' C.

Substitution of nine parts of N-cyclopentyl-fi-chloro propionamide forN-cyclohexyl-fi-chloropropionamide in the foregoing procedure yieldsthe'white crystals of N- cyclopentyl-fi-( l-phenyl 1,2,3,6tetrahydropyridine)pro- CUH5 -HC1 onPoH,

Example 2 A mixture of 10.2 parts of N-cyclohexyl-y-chlorobutyramide,15.9 parts of 4-phenyl-1,2,3,6 tetrahydropyridine, and 0.1 part ofpotassium iodide in parts of toluene is heated in a sealed tube for 72hours at a temperature of -150 C. The reaction mixture is treated withwater, and the organic layer is separated and diluted with ether. Dry,gaseous hydrogen chloride is passed through the solution, whereuponthere is obtained an oily hydrochloride which is collected, dissolved inwater, and treated with sodium hydroxide solution. The liberated base isdissolved in ether and the solution is evaporated to dryness. Onscratching in acetone, a solid is formed The structural formula is whichis then dissolved in diisopropyl ether. Upon standether to yieldN-cyclohexyh'y-(4-phenyl-l,2,3,6-tetrahydropyridine)propionamide meltingat 119.8-12l.6 C.

' Example 3 In an open flask a mixture of 8.4 parts ofu-chloroacetanihde and 15.9 parts of '4-phenyl-1,2,3,6tetrahydropyridine in 200 parts of isopropanol is refluxed for 7 hours.The solvent is evaporated and the residue is treated with water andether. The ether layer is separated and washed with water, whereuponthere precipitates a (4 phenyl-1,2,3,6-tetrahydropyridin)acetanilidemelting at 120-122.2 C. Dry, gaseous hydrogen'chlo} ride is introducedinto the filtrate toyield an oily'pfecipitate. The salt is firstrecrystallized from isopropanol and then from a mixture 'of 720 parts ofisopropanol and 200 parts of acetone to yielda-(4-phenyl-1,2,3,6-tetrahydropyridin)acetanilide hydrochloride meltingat 233.5- 23'5"C.

Example 4 rlnsazsealedireactor a mixture ofl0.5 partsof,B-chloropropionanilide, 15.9 parts 'of 41phenyl-1,2,3,6tetrahydropyridine, and-0.1 part of potassum iodide in 160-parts oftoluene is heated ,for 72 hours ata temperature of 140-150 C. Themixture is treated with water and ether, and the organic layer ,isseparated, dried over anhydrous potassium carbonate, and filtered. Uponpassingdry hydrogen chloride gas through the solution, the hydrochlorideprecipitates. This salt is purified by recrystallization fromacetone toyield (phe nyl 1,2,3,6- tetrahydropyridine)propionanilide -hydrochloride rnelting atr249.5=25.1.5 C.

Example 5 .Substitution-of 10.1 parts of fl-chloro-p-fluoropropion-.anilide for N-cyclohexyl-eachloropropionamide inExam- .ple lyields the,impure hydrochloride which is purified by, recrystallization fromisopropanol to yield B-(4-phenyl- 1,2,3,6 tetrahydropyridine) pfluoropropionanilide hydrochloride melting eat 247-=249 .C.

Example 6 1In a-sealed-reactora mixture of 13-partschop-dichloropropionanilide, 15.9 partsof.4-phenyl-1,2,3,6-tetrahydropyridine, and 0.1 part of potassium iodidein 160 parts of toluene is heated for 18 hours ata temperature 05140-150" C. Thereaction mixture is cooled, treated with l000partsofwater and 4-00 parts of ether, and filtered. The remaining solid isrecrystallized from diisopropyl ether'to yield[3-(4-phenyl-l,2,3,6-tetrahydropyridine)-o-chloropropionanilide meltingatl30.6-l3l.6 C. From the filtrate the organic layer is separated,driedover anhydrous potassium carbonate, and filtered. Anhydroushydrogen chloride gas is introduced into-the solution, whereupon thereprecipitates the hydrochloride which is thenwcollected andrecrystallized from a mixture of equal parts of acetone and isopropanolto yield {3-(4-phenyl- 1,2,3,6 tetrahydropyridine) ochloropropionanilide melting at 201202.5 C.

Example 7 .Example'8 Substitution of 11 partsoffi,p-dichloropropionanilide for B-chloropropionanilide in Example 4yields 5-(4- 'phenyl 1,2,3,6 tetrahydropyridine) chloropropionanilide'hydrochloride melting at 253-4545 C.

{Example 9 .i'Substitution 01515.1 parts of fi-chloro-p-bromopropion-.anilideand 17.8 parts of fi-chloro p-iodopropionanilidefor.B-chloropropionanilide,in the procedure used inr-Example v4 yields,8-(4-phenyl-1,2,3,6-tetrahydropyridine)-pbromopropionanilidehydrochloride, and B- (4 phenyl- 1','2;3,'6 tetrahydropyridine) .piodopropionanilide, respetttively.

4 Example I A mixture of 10.5 parts of p-chloro-o-propionotoluide, 15.9parts of 4-phenyl-1,2,3,G-tetrahydropyridine, and 0.1 part of potassiumiodide in 160 parts of toluene is heated in a sealed reactor for 72hours at a temperature of 140- 150 C. After cooling and decantation, theoily precipitate is treated with water and ether. A sodium hydroxidesolution is added after which the aqueous layer is extracted withdiisopropyl ether. At about 15 C., 5 (4 phenyl 1,2,3,6tetrahydropyridine) o propionotoluide crystallizes. The base melts at122.5- 123.4 .C.

Example 11 Substitution of 9.9 parts of fi-chloro-m-propionotoluide forN-cyclohexyl-B-chioropropionamide in Example 1 yields a crude productwhich is recrystallized from a mixture of 300 parts of benzene and partsof isopropanol to yield 8 i-phenyl 1,2,3,6 tetrahydropyridine)m-propionotoluide hydrochloride melting at '239.S 240.5 C.

Example 12 Substitution of-lO parts of fl-chloro-p-propionotoluide forthe 18,0-dichloropropionanilide in Example 6 yields 5 a (4 phenyl l,2,3,6 tetrahydropyridine) p propionotoluide melting at 155-156 C. and3-(4-phenyl- 1,2,3,6 tetrahydropyridine) p propionotoluide hydrochloridemelting at 252-2535 C.

Example 13 Tue comb a mixture of 11.5 parts of e-chloro-onitropropionanilide, 15.9 parts of 4-phenyl-1,2,3,6-tetrahydropyridine,and 0.1 part of potassium iodide in 80 parts of toluene is heated for 50hours at a temperature of C. The reaction mixture is cooled and thentreated with water and ether. The ether layer is separated, dried overanhydrous potassium carbonate, and filtered. The crude product isobtained by passing anhydrous hydrogen chloride gas through thesolution. The hydrochloride is boiled with a-mixture of 96 parts ofisopropanol and 240 parts of acetone. The resulting suspension isfiltered, and the filtrate is cooled to yield [3-(4-phenyl-1,2,3,6-tetrahydropyridine)-o-nitropropionanilide hydrochloride. Theremainingsolid is recrystallized from methanol to yield'a second crop melting at196.4-198 C.

Example 14 Substitution of 9.9-parts of -chlorobutyranilide for theN-cyclohexyl-jS-chloropropionamide used in Example 1 yields anoily-precipitate which is solidified by treatment with acetone. Theresidue is recrystallized from an equal parts'rnixture of acetone andmethanol to yield 'y-(4-phenyl l ,2,3 ,6-tetrahydropyridine)butyranilide hydrochloride melting at 211213.5 C.

Example 15 A mixture of 11 parts of y-chloro-prfluorobutyranilide, 15.9parts of 4-phenyl-l,2,3,6-tetrahydropyridine, and 0.1 part of potassiumiodide and 80 parts of toluene is heated in abomb for 80 hours at atemperature of l35-l50 C. The contents of the bomb are taken up inwaterand ether. The aqueous layer is separated and extracted Example 16In a sealed reactor a mixture of 10.3 parts of 'y-chloro-B-methylbutyranilide, 15.9 parts of4-pl1enyl-1,2,3,6-tetrahydropyridine, and 0.1 part of potassium iodidein 100 parts of toluene is heated for 60 hours at a temperature of140-150 C. The reaction mixture is cooled and filtered. To the filtrateare added 500 parts of hy-- Example 17 In a bomb a mixture of 11.4 partsof N-methyl-B-chloropropionanilide, 15.9 parts of4-phenyl-1,2,3,6-tetrahydropyridine, and 0.1 part of potassium iodide in160 parts of toluene is heated for 70 hours at a temperature of 140-150C. The contents of the bomb are cooled and treated with water and ether.The organic layer is separated, dried over anhydrous potassiumcarbonate, and filtered. Dry, gaseous hydrogen chloride is introducedinto the solution. The resulting precipitate is collected on a filterand purified by recrystallization from acetone to yield N-methyl-p-(4-phenyl-l,2,3,6-tetrahydropyridine)propionanilidehydrochloride.

Substitution of 13 parts of: N-propyl-B-chloropropionanilide for theN-methylpropionanilide in the foregoing procedure yields the whiteprismatic crystals of N-propylfl (4-phenyl1,2,3,6-tetrahydropyridine)propionanilide hydrochloride of thestructural formula CaH! 6 7 What is claimed is: l. A compound of thestructural formula wherein A is a member of the class consisting ofcyclopentyl, cyclohexyl, phenyl, halophenyl, nitrophenyl, and tolylradicals, B is a member of the class consisting of hydrogen and loweralkyl radicals, and All: is a lower alkylene radical.

2. A compound of the structural formula wherein Alk is a lower alkylenegroup.

3. B (4-phenyl-1,2,3,6-tetrahydropyridine)propionanide.

4. -y-(4-phenyl-l,2,3,6-tetrahydropyridine)butyranilide. 5. A compoundof the structural formula Halogen CHI-CH2 wherein All: is a loweralkylene group.

9. N cyclohexyl 1 (4 phenyl l,2,3,6 tetrahydropyridine)butyramide.

No references cited.

1. A COMPOUND OF THE STRUCTURAL FORMULA